Intermediates useful in the synthesis of alpha-lipoic acid



INTERMEDIATES USEFUL INY'IIHE SYNTHESIS or a-LIPDIC cm Frederick WHolly, Cranford, Arthur Wagner, Princeton, and E Zdw ar'd Walton andCarl H; Holfman scutch Plains, N. .L, assignors to Merck & "Co., Inc.,Rahway, N. J; acorporation of NewJersey' No Drawing. ApplicationFebruary 19, 1957 Serial No; 641,013 9 Claims. 01. 260481) invention isconcerned with the production of novel 6,8-(hydrocarbon substitutedmercapto) -5-oxoca-' prylic acids having the formula-- i Y H:QHzQHz-OHC(CHQMCOOH Rf SR and salts and esters thereof, wherein. R and Rare the same or different hydrocarbon substituents such as alkyl,alkenyl, alkynyl, aryl and aralkyl groups. This invention is alsoconcerned with novel processes for producing these compounds in whicha,' -(hydrocarbon substituted mercapto)-butyryl halides: are used as thestartf ing materials. In addition, this i with novel intermediatesuseful in producing the 6,8- (hydrocarbon substitutedmercapto)--oxocapry1ic acids.

This application is a continuation-in-part of our c0- pendingapplication Serial No. 396,334, filed December 4, 1953 now United StatesPatent No. 2,809,978.

The novel, 6,8-(hydrocarbon substituted mercapto )-5- oxo cap r ylicacids are valuable in the production of other novel chemical compoundsand are, particularly important as precursors in the synthesis ofu-lipoic acid or 5- [3-(1,2-dithiacyclopentyl)] pentanoic acid as willbe shown hereinafter. In this regard 5[3-(1,2-dithiacyclopentyl) Ipentanoic acid, is a valuable growth stimulating crystalline substancewhich was first obtained from liver and later found to have thestructure-- eHT0H='oH(oHz),o00II S-- j asdisclo'sed in the I. Am. Chem.Soc. 74,, 3455 (1952).

initial reaction is illustrated as follows:

, 00012 0 omomoncox n Y H omornonconooom SR SR 000m sn SR 00011 I II IIIwherein X represents a halogen, Y represents an alkali metal, alkalineearth metal or alkoxymagnesium and R, R, R and R represent the same ordifferent hydrocarbon substituents such as alkyl, alkenyl, alkynyl, aryland aralkyl groups.

The diesters of 4,6-(hydrocarbon substitutedmercapto)-2-carboxyd-oxocaproic acids are then converted to the,corresponding. 4,6:(hydrocarbon substituted merinvention is concerned2,875,239 Patented Feb. 24, 1959- 2, capto)-3-ox0caproic acidsand estersto the reactions thereof according 0 i ll 5 omomonoomooom r 7! SR SR erv CHgQI'ItCHCCHCOOR i SR S'R 00011 i 10 (I? ornomcnoomooorr SR SR InIV-A wherein R, R, R and R have the significance previously assignedThe. 4,6-(hydrocarbon. substituted mercapto)-3.-o xocaproio acids are vsubsequently reacted, in the form, of an ester or salt with a suitablederivative of acrylic, acid,

such as an;amide,-nitrile, ester or salt to form the corresponding,derivative; of 6,8-(hydrocarbon substitutedmercapto)4ecarboxy-i-oxocaprylic acid, which reaction can be illustrated: asfollows:

20 CHnGHiCHCHzCOOR CH2=CHR -b SR s3 V VI 0 3O OHzCHaCHiCHCHzCHaR SR S R00011 VII wherein R and R have the meaning previously assigned, Rrepresents an alkyl, aryl or aralkyl group or a metal and R representsthe cyano, carbamylancl COOR groups wherein R has the same significanceassigned herein.

Thefourth and last reaction comprises a simultaneous hydrolysis anddecarboxylation of the derivatives of the 6,8;(hydrocarbon substitutedmercapto)-4-carboxy-5-oxocaprylic acids to produce the desired 6,8-(hydrocarbo n substituted mercapto )-5-oxocaprylic acids as illustratedbythe following reaction:

o 0 -15 I I omornonb ortornorncm omomonb 011930 0 on SR e12 001: SR SRVII VIII wherein R, R, R and R have the meaning given above.

The initial reaction of this process in which an ,7- (hydrocarbonsubstituted mercapto) -butyryl halide (I) is reacted with a salt of amalonic acid diester (H) to prepare a diester of 4,6-hydrocarbonsubstituted mercapto)-2-carboxy-3-oxocaproic acid (III) may beconveniently achieved by contacting the reactants in the presence of aninert solvent. For this purpose, inert solventssuch as the lower alkylethers like ethyl ether and isopropyl ether, chloroform, saturatedhydrocarbons such as pentane and hexane, benzene and. toluene areparticularly suitable preferably when substantially free of water. Themixture of reactants in a suitable solvent is ordinarily heated to anelevated temperature to effect the reaction and, in this regard, thereflux temperature 0 may be used with good results. Under theseconditions the reaction is completed in less than one hour. Followingcompletion of this reaction the desired diester of 4,6-(hydrocarbonsubstituted mercapto)-2-carboxy-3- oxocaproic acid may be isolated fromthe reaction turebyconventional methods as distillative removal of thevsolvent. It is preferred, however, not to isolate this product fromthereaction mixture but, instead to i immediately subject the productpresent in the reaction mixture to conditions which effectdecarboxylation of The described reaction may be conveniently effectedusing any suitable, :,1-(11Yd106211b0n substituted mercapto) -butyrylhalide as the starting material. Thus, the oc,'y-hyd1'OCarb0I1substituents may be the'same or different alkyl, alkenyl, 'alkynyl, aryland aralkyl radicals. In this regard, it is generally preferred toemploy those compounds as starting materials which have identicalhydrocarbon substituents. Such compounds are referred to herein asbis-substituted. In addition, the any-bis- (lower alkylmercapto andlower alkenylmercapto) bu tyryl halides are particularly useful in thesynthesis of u-lipoic acid. Specific examples of hydrocarbonsubstituents which may be present on these starting mate" rials aremethyl, ethyl, propyl, butyl, t-butyl', allyl, butenyl, pentenyl,heptenyl, ethynyl, propynyl-2, phe'ny l, benzyl and similar groups. 7preferably achieved with halides of the type described in which thehalogen substituent is either chlorine or bromine. v

Salts of malonic acid diesters which may be used in this invention thatmight be mentioned are the alkoxymagnesium derivatives of malonic aciddiesters or the alkali metal and alkaline earth metal enolates. Theester groups of such salts may be either the same or different alkyl,aryl and aralkyl groups and are preferably lower alkyl groups. Somespecific examples of such salts which may be used as reactants in thisprocess are dimethyl methoxy magnesium malonate, diethyl ethoxymagnesium malonate, diphenyl and dibenzyl ethoxy magnesium malonate,ethylt-butyl ethoxy magnesium malonate, and sodium, potassium, calciumand magnesium salts of dimethyl, diethyl, diphenyl, dibenzyl and similarmixed esters of malonic acid.

f The reaction described may be used to prepare any desired diester of4,6-(hydrocarbon substituted mercapto)- 2-carboxy-3-oxocaproic acid. Ina specific illustration of this reactiona,'y-bis(methylmercapto)-butyryl chloride is reacted with ethyl t-butylethoxy magnesium malonate to obtain tertiary butyl4,6-bis(methyimercapto)-2-carbethoxy-3-oxocaproate. Examples of similarcompounds which are prepared in this manner from i the appropriatereactants aremethyl-4,6-bis(ethylmercapto)-2-carbornethoxy-3-oxocaproate,ethyl4,6-bis(ethylmercapto)-2-carbethoxy-3oxocaproate,ethyl-4,6-bis(allylmercapto) 2 carbethoxy 3 oxocaproate,- methyl- 4,6bis(2 methyl l ethyl 2 butene mercapto)-2- carbethoxy 3 oxocaproate,propyl 4,6 bis ('3 methyl 2 ethyl 2 pentene mercapto) 2 carbomethoxy-3-oxocaproate,'phenyl-4,6-bis(phenylmercapto)-2-carbophenoxy-B-oxocaproate,ethyl-4,6-bis(benzylmercapto)-2- carbethoxy-3-oxocaproate,benzyl-4,6-bis(propargylmercapto)-2-carbobenzyloxy-3-ox0caproate,methyl-4-ethylmercapto 6 propylmercapto 2 carbomethoxy 3- oxocaproate,and the like.

According to the second step of this process the diesters, preferablythe lower alkyl diesters, of the 4,6- (hydrocarbon substitutedmercapto)-2-carboxy-3-oxocaproic acids (III) produced above areconverted to the corresponding mono-esters of 4,6-(hydrocarbonsubstituted mercapto)-3-oxocaproic acid (IV). This conversion in whichthe Z-carboxy group is eliminated from the caproic acid moiety isattained by either an acid catalyzed reaction or by thermaldecarboxylation to the desired product.

Acid catalyzed decarboxylation is preferably achieved under solventconditions in the presence of a suitable acid. Thus, this reaction isconveniently effected by contacting the diester of the 4,6-(hydrocarbonsubstituted mercapto)-2-carboxy-3-oxocaproic acid in inert sol ventssuch as ethers, benzene, hexane, chloroform and the like with catalyticamounts of acids such as. alkyl.

In addition, this reaction is I and aryl sulfonic acids and particularlypara-toluene sulfonic acid. In this regard, the use of substantiallyanhydrous conditions is sometimes preferably for optimum results.Elevated temperatures above C. and up to the reflux temperature are usedfor the decarboxylation. Under such conditions the reaction is completedin an hour or two and the product formed may be recovered from thereaction mixture by the usual methods. Thus, the solvent may beevaporated and the oily product purified by distillation under reducedpressure. 1

More specifically, this transformation is'illustrated by the conversionof t-butyl-4,6-(methylmercapto)-2-carbethoxy-3-oxocaproate in benzene atreflux temperature to ethyl-4,6-bis(methylmercapto)-3-oxocaproate.Representative of other similar compounds which are produced accordingto this decarboxylation reaction from the appropriate reactants aremethyl-4,6-bis(ethylmercapto)-3- oxocaproate,ethyl-4,6-bis(ethylmercapto)-3-oxocaproate, ethyl 4,6 bis(allylmercapto)3 oxocaproate, methyl- 4,6-bis(Z-methyl-1-ethyl-2-butenemercapto)-3-oxocaproate, propyl-4,6-bis(3-methyl-2-ethyI-Z-pentenemercapto)- 3-ox0caproate, phenyl-4,6-bis(phenylmercapto)-3-oxocaproate,ethyl-4,6-bis(benzylmercapto)-3-oxocaproate,benzyl-4,6-bis(propargylrnercapto)-3-oxocaproate, methyl-4-ethylmercapto-6-propylmercapto-3-oxocaproate and the like.

As has been indicated above, this decarboxylation is also effected bythermal cracking. According to this procedure diesters of the4,6-(hydrocarbon substituted mercapto)-2-carboxy-3-oxocaproic acids areheated at a suitable elevated temperature, preferably in the neigh' borhood of about 150300 C., to accomplish removal of the 2-carboxy groupand form the corresponding mono-esters. ,After the conversion has beenaccomplished the product may be recovered by conventional methods andpurified. By proper selection of the reactants those mono-esterspreviously named herein and other similar compounds can be produced bythis procedure.

The esters of 4,6-(hydrocarbon substituted mercapto)- 3-oxocaproic acidsare readily converted to the corresponding alkali metal and alkalineearth metal salts such as sodium, potassium, calcium and magnesium saltsby hydrolysis of the ester with an alkali or alkaline earth metal base.The salts in turn are converted to the free acids by hydrolysis withmineral acids such. as hydrochloric acid and sulfuric acid.

The third reaction of this process is directed to the production ofvarious derivatives of 6,8-(hydrocarbon substitutedmercapto)-4-carboxy-5-oxocaprylic acids such as nitriles, amides,diesters and dimetal salts thereof (V-II) Such compounds may beconveniently prepared by reacting an ester or salt of a 4,6-(hydrocarbonsubstituted mercapto)-3-oxocaproic acid (V) prepared as above with aderivative of acrylic acid (VI) under suitable reaction conditions. Thisreaction may be readily effected by contacting the reactants in thepresence of a suitable solvent, preferably an alcohol such as the loweralcohols like methanol and ethanol. Ordinarily a small amount of aquaternary ammonium hydroxide such as trimethyl benzyl ammoniumhydroxide (Triton B) or an alkali metal alk-.

oxide is added to the mixture to promote the reaction. To prevent undueside effects the temperature is ordinarily controlled below C. After thereactants have been combined, preferably using approximately equimolaramounts of each reactant, the mixture is continually stirred for 12 to60 hours during which time an elevated temperature below 60 C. ismaintained. Upon completion of the reaction the desired product may berecovered from the reaction mixture .by extraction with an immisciblesolvent such as chloroform, evaporation of the solvent and distillationof the product under reduced pressure.

This reaction is conveniently effected with any suitable derivative ofacrylic acid such as acrylonitrile, acrylamide and esters and salts ofacrylic acid such as the a1kyl,-ary1 aai'a'asd and'j'jaralltyl esters,and; alkali metal and jralkaline,

metal. altsfthereqf, More specifically, thegmethyl, ethyl, propyl,butyhphenyl andbenzyl esters andsqdiurn, potassium, magnesium and?calciumsalts of, acrylic acid are examplesoij cpmpounds which may be,used in this reac tion..

Spe fi 11 lu t ative off ethyl bis(m ethy lmerc apto)- 3 oxocaproatewith methyl aeryl itelto produce. methyl-6,8-bis (methylmercapto)-4.=carbethexy-ioxocaprylate.. Other. examples of closely: relatedcompounds that are incorporated within the scope of this invention whichare produced according to this method from the appropriate reactantsareethyl- 6-,8-bis ethyl'mercapto.) -4-carbomethoxy-S .oxocaprylate,ethyl-6,8 bis(ethylmercapto)-4-carbethoxy-5 oxocaprylate,methyl-6,8.-bis(methylmercapto)-4-carbomethoxy-5- oitoca'prylate,phenyl*-6,8-bis(phenylmercapto)-4-carbethoXY-S-oxoeaprylate, benzyl-6,8-bis (propylmercapto) 45, carbophe'noxy-i-oxocaprylate,methyl-.6,8-bis(allylmercapto)-4-carbethoxy-S-oxocaprylate,ethyl-6,8-bis (Z-methyl-lethyl-2-butene mercapto)-4carbomethoxy-S-oxocaprylate, propyl-6,8-bis(3-methyl 2-ethyl 2-pentenemercapto)-4- carbppropoxy-S-oxocaprylate,,ethylw6g8-bis(propynylmerw capto)-4-carbethoxy-S-oxocaprylate,methyl-6-ethylmercapto-8 propyl nercapto-4 carbomethoxy- .5 oxocaprylateand alkali metal and alkaline earth metal salts, such as the sodium andpotassium, calcium and magnesium salts and the nitrile and amide ofthese and similar compounds. The freeiacids of such'compounds arereadily obtainedby hydrolysis oftlieinitrile, amide, esters and saltsaccording to conventionalmethods.

Thelast reaction in thisprocess comprises the combined hydrolysis anddecarboxylation of a derivative of 6,8- hydrocarbonsubstitutedmercapto)-4-carboxy-5oxocaprylic acid (VII), such asdescribed above, to the corresponding 6,8-(hydrocarbon substitutedmercapto)--oxocaprylic acid (VIII). This reaction may be convenientlycarriedv outtby treating the reactant with a suitable mineral acid,preferably. in the presence of a carboxylic acid. The reaction, however,is preferably run in a mixture of glacial aceticacidt andhydrochloricacid since theproduct can, bee. readily. recoveredrby;distillation-of such acids. The. reaction proceedsan room temperaturealthough ele vated temperatures are: alsoa-used: with satisfactoryresults. Under such, conditions thereactionlis completed in from about 6to about 60 hours. The reaction product is readily recovered fromthenmixture according to conventional methods such as evaporation andextraction with a suitable solvent such" as chloroform.

The described reaction is specifically illustrated by the eonversion. ofmethyl-6,8-bis(methylmercapto)-4ecarbethoxyfi oxoeaprylate in thepresence of a'mixture of hydroehloric acid. and glacialacetic acid to6,8-bis( nethylmercap toid-oxocaprylic acid. In: a. similar mannertotheromppun t such as-6,8-bis(ethylmercapto) 5-oxocaprylic acid,6],"8bis(propylmercapto)-5roxocaprylic acid, ;6,8-bis-(butylmercapto):S-oxocaprylic acid, 6,8.-bis(phenylmercapto)-5-oxocaprylic acid, .6,8.-bis(benz ylmercapto)-5- oxocapr'ylic acid,6,8-bis(allylmercapto)-5-oxocaprylic acid, 6,S-bis(Z-methyII-ethyl-Z-butene mercapto)-5-oxocaprylic acid,6,8-bis(3:methyl-Lethyl-Zepentene mercapto) -5-oxocapry1ic acid, 6,8-bis(propargylmercapto)-5-oxo caprylic acid, fi ethylmercapto-8propylmercapto-5-oxocaprylic acid and the like are prepared by theproper selection' ofreactants;

Estersfof the 6,8-(hydrocarbon substituted ,mercapto) -5-oxocaprylieacids are conveniently prepared by reacting such compoundswith a suitable halogenating agent to form the correspmiding'acyl halideand subsequently reacting the acyhhalide with an alkanol, aryl alcohol,or aralkanol'to obtainthe desired ester. The acyl halides or the"6,8hydrocarbon substituted mercapto)-5-oxocaprylates may be, convenientlyprepared. by known methods such as by-reacting the'acidwith halogenatingagents such as thionyl chloride, phthalyl chloride, phosof this method.is the reaction ether, chloroform or benzene. Esters pho stfich qiidhisn l br de and p slr bromide in thepresence oi, conventional solventsor' an excess halogenation may be achieved at 0-10. C. or at a moreelevated temperature. if desired. After the acyl halide has beenprepared it is recovered from thereaction mixture and esterified byreaction with an excess of the appropriate alcohol under acidicconditions. The esters formed in. this manner are recovered from thereaction mixture by ordinary procedures.

Examples of some 6, 8 -(hydr ocarbon' substituted mercapto)-5-oxocaprylic acid esters which may be prepared from thecorresponding acid and intermediate acyl. halides such as the bromideandchloride that might be mentioned aremethyl-6,8-bis(methylmercapto)-5-oxo caprylate, methyl- 6, 8-bis ethylrrercapto 3-oxocaprylate; ethyl-6,8bis (ethyimercapto)-5-oxocaprylate,benzyl-6,8- bis(propylmercapto) 5 oxoeaprylat, propyl 6,8 -,bis(butylmercapt o) -S oxocapryIate, I phenyl-6,8-bis(phenylmercapto)S-oxocaprylate, methyl -6,8-bis(benzylmercap to) 5 oxocaprylate, methyl-.6,8 bis(allylmereapto)- S oxocaprylate, ethyl i oxocaprylate, methyIG-ethylmercapto-S-propylmercapto- S-oXocapryIate and the like, l Loweralkyl estersare also conveniently produced by reacting a 6,8-(hydrecarbon substituted mercapto)-5-oxocaprylic acid with adiazoalkene, such as diazomethane or diazoethane, in a suitable dryinert. solvent such as may alsobe produced by reaeting the aeid with asuitable alcohol under acidicconditions according .to tl e classicalmethod of producingesters. The resulting esters, like.the acidsflarewater insoluble oils which may be purified by distillation underreducedpressure l l In additior to esters, salts of the 6,8-(hydrocarbonsubstituted mercapto)-5- oxocaprylic acids may also be produced. Forexample, the alkali metal and alkaline earth metal salts maybe preparedby contacting a, suitable organic solventselution of a 6,8 (hy drocarbonsubstituted mercapto)- 5.-oxo caprylic acid with an aqueous solution ofan alkali metal or alkaline earth metal hydroxide, bicarbonate orearbonate. The salt is readily recovered fro m the aqueous phase byevaporation to y Inthis manner ss s u h ss hs q P9- tassiurn, calciumand magnesium salts, of 6,8-(hydrocarbon substituted.mercapto)-5-oxocaprylic acids, such as those specifically named.hereinbefore, may be prepared.

According to a furtl er embodiment of this invention diesters of6,8-(hydroearbon substituted mercapto)-4-.

carboxy-S-oxocaprylic acids may also be produced by reacting an ester ofa 4,6- (hydro carbon substituted mercapto)-3-oxocaproic acid with anester of a S-halo prepionic acid. This. reaction may be. illustrated asfollows:

1 momenixomooom xomomooom sR' SR aryl and aralkyl groups, and X ishalogen t This reaction is-preferably effected by contacting. the

reactants in the presence of; a, suitable inert organic solvent which isanhydrous or substantiallyfree of water. Amongthe. solvents which may beused for this purpose are ethereal solvents such as. dioxane',tetrahydrofuran.

and ether alcohols such as methanol, and ethanol, .be,n-, zene, tolueneand hexane. Approximately, equiinolar quantities of the reactants arepreferably 'employed'in the reaction together with about equiniolarquantityof ofthe halogenating agent if it isa liquid. This 6,8 bis(propargylmercapto) 5 andR represent the. same.

an enolizing agent such as sodamide, sodium triphenylmethyl and sodiumand potassium alkoxides such as methoxide or ethoxide. The reaction isconveniently accomplished at elevated temperatures such as the refluxtemperatures of the mixture. Under such conditions the reaction isordinarily completed in from about one to five hours, usually two hoursbeing entirely adequate. Following completion of the reaction themixture is preferably acidified with a mineral acid such as sulfuricacid or hydrochloric acid to decompose any excess base present and toaid the recovery of the desired product. The product may then berecovered according to the ordinary techniques.

This reaction is conveniently accomplished employing esters of B-halopropionic acid in which the ester substituent is an alkyl, aryl oraralkyl group such as methyl, ethyl, propyl, phenyl and benzyl radicalsand in which the fl-halo substituent is chlorine or bromine.

The application of this alternative procedure may be conveniently usedto prepare those diesters of 6,8-(hydrocarbon substitutedmercapto)-4-carboxy-5-oxocaprylic acids previously disclosed herein andother similar novel 7 compounds.

The 6,8-(hydrocarbon substituted mercapto)--oxocaprylic acids producedaccording to the present invention may be converted to5-[3-(1,2-dithiacyclopentyl)] pentanoic acid, also called u-lipoic acid,by the utilization of a process which is the joint invention of Hollyand Wagner and is disclosed in United States patent application SerialNo. 396,333, filed December 4, 1953. This process comprises essentiallyreacting a 6,8-(hydrocarbon substituted mercapto)-5-oxocaprylic acidwith an alkali metal borohydride to produce the corresponding6,8-(hydrocarbon substituted mercapto)-5-hydroxy caprylic acid whichimmediately forms the corresponding S-membered lactone, reducing saidlactone with phosphorous-iodine to produce a 6,8-(hydrocarbon substituted mercapto) caprylic acid, and reacting said compound Withdealkylating agents such as 50% sulfuric acid or thiouronium bromide andoxidizing the resulting material with I KI to obtain 5-[3-(1,2-dithiacyclopentyl)] pentanoic acid.

In the practice of the present invention, the seq-(hydrocarbonsubstituted mercapto) butyryl halides which are used as startingmaterails may be conveniently prepared according to novel methodsdisclosed in the United States patent application of Arthur F. Wagner,Serial No. 369,535, filed July 21, 1953, now U. S. Patent No. 2,842,587.

The following examples are given for purposes of illustration and not byway of limitation:

EXAMPLE 1 Tertiary butyl-4,6-bis(methylmercapto) -2'-carbethoxy-3-axocaproate bethoxy-3-oxocaproate is diluted wtih 60 ml. of water andacidified with ml. of 2 N sulfuric acid. The ether phase is separatedand the aqueous phase is ex tracted with ether. The combined etherextracts are washed with water, dried over anhydrous magnesium sulfate,and the ether removed. Final traces of water are removed by azeotropicdistillation with benzene.

The u,'y-bis(methylmercapto) butyryl chloride used in this example maybe conveniently prepared according to the following representativeprocedures using oxallyl chloride and thionyl chloride asthehalogenating agents:

A. About 10.7 grams of sodium d,'y-bis(m'ethylm'er capto) butyrate issuspended in35 ml. of dry benzene of 'thionyl chloride added thereto.After standing at about 0 C. for one hour the mixture is evaporated atroom temperature under reduced pressure to remove thionyl chloride andvolatile side products. The aflbis(methylmercapto) butyryl chloride isobtained as an oil.

, EXAMPLE 2 Tertiary butyl 4,6 bis(t butylmercapto) 2carbeth0xy-3-0x0capr0ate In 100 ml. of anhydrous ether 18.8 grams ofethyl t-butyl malonate is reacted with 11.4 grams of magnesium ethylateto produce ethyl t-butyl ethoxy magnesium malonate. To this solution isthen added 33.8 grams of a,v-bis(t-butylmercapto) butyryl chloride in100 ml. of ether and the mixture refluxed for one hour. Tertiarybutyl-4,6-bis(t-butylmercapto)-2-carbethoxy-3- oxocaproate is obtainedand is isolated as in Example 1.

EXAMPLE 3 Tertiary'butyl 4,6 bis(allylmercapt0) 2 carbethoxy-3-0x0capr0ate I To'200 ml. of anhydrous ethyl ether is added 37.6 gramsof ethyl t-butyl malonate and 22.2 grams of mag nesium ethylate. Themixture is refluxed for 30 minutes and to the solution of ethyl t-butylethoxy magnesium malonate is added 55 grams of a,'y-bis(allylmercapto)butyryl chloride in ml. of ether. The mixture is refluxed for 30minutes, cooled and t-butyl-4,6-bis(allylmercapto)-2-carbethoxy-B-oxocaproate isolated as described inExample 1.

EXAMPLE 4 Tertiary butyl 4,6 bis(benzylmercapto) 2 curbw methoxy 3oxocapraate Following the procedure of Example 1, 26.1 grams of methylt-butyl malonate is reacted with 17.1 grams of magnesium ethylate in 100ml. of ether to form methyl t-butyl ethoxy magnesium malonate. Themixture in turn is combined with 59.6 grams of a,'y-bis(benzylmercapto)butyryl chloride in 100 ml. of ether and reacted according to thisprocedure to produce t-buty1-4,6-bis-(benzylmercapto)-2-carbomethoxy-3-oxocaproate.

EXAMPLE 5 Ethyl-4,6-bis(methylmercaplo) -3-0x0capr0ate Aftersubstantially all the water is removed from the benzene solution is thenwashed with saturatedaqueous sodium bicarbonate and with water. Thebenzene so-, lution is dried over magnesium sulfate and the benzeneremoved by evaporation under reduced pressure. The oily residue isdistilled to obtain ethyl-a,'y-bis (methylmercapto) -3'- oxocaproate;boiling point -1 14. C. .05

25; (E% =122 molecular weightfound 255:3; (calc.

EXAMPLE 6 Ethyl-4,6-bis(t-butylmfdapt0)-3-oxacaproate in Example 5.

. EXAMPLE 7. Ethyl-debts all lrfierca to PLE 9 Methyl 6,8bis(metizylriiercapto A solution of 20 grams! of?ethyl-4,6-bis(methylmercapto)-3-oxocaproate;and five grams.of 30%methanolic trimethyl benzyl ammonium hydroxide (Triton. B) is stirredWhile seven grams of methyl acrylate is added over a 15-minute period.During this addition the temperature rises to about 35 C. and soonincreases to 50 C. The reaction is held at about 50 C. for 48 hoursafter which it is cooled and extracted with chloroform. The chloroformsolution is washed with 50 ml. of 1 N hydrochloric acid, water andfinally dried over anhydrous magnesium sulfate. The ether is removed andthe residual oil is distilled to obtainmethyl-6,8-bismethylmercapto)-4-carbethoxy-S-oxocaprylate.

EXAMPLE 10 Methyl 6,8 bis(t butylmercapto) 4 carbethoxy 5- oxocaprylateA methanol solution of 25.1 grams ofethyl-4,6bis(tbutylmercapto)-3-oxocaproate is prepared and to it isadded 6.4 grams of methyl acrylate and 4 grams of 30% methanolictrimethyl benzyl ammonium hydroxide. The mixture is maintained at about50 C. for 20 hours and the methyl-6,8-bis (t-butylmercapto)-4-carbethoxy-5-oxocaprylate recovered by the procedure of Example 9.

EXAMPLE 11 Methyl6,8-bis(allylmercapt0) -4-carbelhoxy-5- oxocaprylate Toa solution of 36 grams of ethyl-4,6-bis(allyhnercapto)-3-oxocaproate inmethanol is added 10.5 grams of methyl acrylate and 7 grams of 30%methanolic trimethyl benzyl ammonium hydroxide. The mixture is kept atabout 50 C. for one day and then extracted with ether. The product isworked up in the usual manner to obtainmethyl-6,8-bis(allylmercapto)-4-carbethoxy-5-oxo caprylate.

1.5. grams 10f" petoluener sulfonic acid: and? the-Ethyl-l4,6-bis(t-butyl'-. mercapto)-3-oxocaproate is formed:' and:recovered. as

EXAMPLE 13 6,8bis(methylmercapto)Jmxaeaprylic acid A solution of 6.8grams of methyl-6;8--bis(methylnrer capto)-4-carbethoxy 5-oxocaprylatein 100 ml." of glacial acetic acid and, 24 ml. atconcentrated"liydrochlorioapid is preparedand allowed-to stand at roomtemperaturefor 48 hours. pressure, the residue extracted withaqueoussodium 'hicarbonate, the extract acidified and extracted withchloreform. The chloroform is it removed and the residue is dissolved in50 ml. of cold 1 N sodium hydroxide and allowed to stand at about 6C.overnight. The mixture is acidified to pH 3 withconcentratedhydrochloric acid and extracted with chloroform. Thechloroform is removed and the product heated at 85 C. for 1 hours toeliminate carbon dioxide. The resulting6,8-bis(methyhnercapto)-5-oxocaprylic acid has ultra violet absorptionmaxima at 2 390 A. (E.% 27.7) and 2970 A. (E% 15.5).

EXAMPLE 14 6,8-bis(tbutylmercapto)-5-oxacaprylic acid Methyl 6,8 'bis(tbutylmercapto) 4 carbethoxy- S-oxocaprylate is reacted according tothemethodof Example 13 to form.6,8-bis(t butylmercapto).-5oxocaprylic acid.

' EXAMPLE. 15 1 6,8-bis(allylmercapt0)5-0xocaprylic acid EXAMPLE 16 I6,8-bis(benzylmercapto) -5-ox0capry.lic acid Five grams ofmethyl-6,8-bis (benzylmercapto)-4-carhomethoxy-S-oxocaprylate is addedto a mixture of 75 ml. of glacial acetic acid and 20 ml. of concentratedsulfuric acid and the mixture allowed to stand.6,8-'bis(-benzylmercapto)-5-oxocaprylic acid is formed and recovered asin Example 13.

EXAMPLE 17 M ethyl-6,8-bis( methy lmercapto) -4-carbeth0xy-5oxocaprylate using methyl-p-chloropropionate To a solution of 4.5 gramsof sodium meth'oxide in ml. of methanol is added 20 grams ofethyl-4,6-bis (methylmercapto)-3-oxocaproate. The resulting solution isrefluxed and to it is added 9.8 grams of methyl-fi-chloropropionate overa ten-minute period. Refluxing is continued for two hours with stirring.The mixture is cooled and acidified to pH 3-4 with a cold solution ofhydrochloric acid. The acidified mixture is diluted with ice water andextracted with chloroform. The chloroform extracts are washed with waterand dried over anhydrous magnesium sulfate. The chloroform is evaporatedand the residual oil distilled to give substantially pure methyl 6,8bis(methylmercapto)-4-carbethoxy 5 oxocaprylate; boiling point -I60C./50 mm., n =l.5028.

Any departure from the above description which con- The .mixture isconcentrated under reduced- 1 1 forms to the present invention isintended to be included within the scope of the claims.

What is claimed is: 1. A compound having the structural formula:

II OHaCHaCHCCHC OR SR SR 0 O O R CHflCHiCHC 001 SR SR with a compoundhaving the formula:

0 0 0 B. You

thereby producing a compound having the formula;

CHzGHnCHCHCOOR SR SR 000R wherein Y is a member of the class consistingof alkoxy magnesium, alkali metal, and alkaline earth metalsubstituents, R and R are selected from the class consisting of loweralkyl, lower alkenyl, phenyl and benzyl having the formula:

groups, and R and R are members of the class consisting of alkyl, aryland aralkyl groups.

7. The process which comprises heating a orgy-bis chloride with acompound (loweralkylmercapto) butyryl to produce a4,6-bis(loweralkylmercapto)-2-carboxy-3-' oxocaproic acid diesterwherein Y is -a member of the class consisting of alkoxy 'megnesium,alkali metal and alkaline earth metal substituents, and R and R arelower alkyl.

8. The process which comprises heating a,'y-bis( methy1- mercapto)butyryl chloride with a compound having the formula: V

YCH

to produce a 4,6-bis(methylmercapto)-2-carboxy-3-oxocaproic acid diesterwherein Y is a member of the class consisting of alkoxy magnesium alkalimetal and alkaline earth metal substituents, and R and R are loweralkyl.

9. The process which comprises heating a,' -bis(allylmercapto) butyrylchloride with a compound having the formula:

H (300m to produce a 4,6-bis(allymercapto) -2-carboxy-3-oxocaproic aciddiester wherein Y is a member of the class consisting of alkoxymagnesium alkali metal and alkaline earth metal substituents, and R andR are lower alkyl.

7 References Cited in the file of this patent Walker et aL: J..A. C. 8.,vol. 68, pp. 1386-9 (1952).

1. A COMPOUND HAVING THE STRUCTURAL FORMUAL: